ES2205166T3 - DERIVATIVES OF ISOQUINOLINE AND MEDICINAL PRODUCT. - Google Patents

Abstract

The invention relates to a compound of the following general formula ÄIÜ or a medicinally acceptable salt thereof, or a solvate thereof, <CHEM> wherein R<1> represents alkyl, alkenyl, alkynyl, alkoxy, hydroxy, cyano, or halogen; R<2> represents hydrogen, hydroxy, or halogen; R<3> represents hydrogen, alkyl, or amidino; Ring A represents a 5 to 11-membered cyclic amino group which may be substituted, which cyclic amino group may be bridged between two carbon atoms in optional positions. The compound of this invention is useful for the prevention or treatment of cerebral tissue impairment due to the vasospasm following cerebral hemorrhage.

Description

Isoquinoline derivatives and medication.

Area of application

The present invention relates to a derivative of isoquinoline that has a vasospasm inhibitory activity brain and therefore can be applied in the form of medicine.

Background

Cerebral vascular diseases can subdivide into the hemorrhagic group and the ischemic group. The group hemorrhagic includes, for example, subarachnoid hemorrhage caused by an aneurysmal rupture, cerebral hemorrhage hypertensive and cranial trauma. Subarachnoid hemorrhage It consists of a delayed vasospasm of the main arteries brain and can lead to vascular constriction disorders and Sometimes to death. The ischemic group includes the infarction cerebral and transient ischemic attack (TIA). Disorder vascular and neuronal injury caused by heart attack or bleeding can lead to dyskinesia and dysfunctions neurological and mental in the acute and chronic state, with disturbance of consciousness and even death as the outcome of severe cases

For the treatment of such diseases cerebral vascular drugs are currently being used antithrombotic and brain circulation enhancers and metabolism. However, there are few available drugs that inhibit this fatal cerebral vasospasm or neuronal injury that leads to dementia and there is a pressing need to find effective therapeutic agents.

By way of illustration, when a subarachnoid hemorrhage a narrowing of the light occurs vascular that persists for several weeks in the main cerebral arteries in the 4 - 5 days after the episode hemorrhagic. This phenomenon is known as cerebral vasospasm and a Once recent ischemia triggers the start-up of symptoms neurological, functional prognosis and, sometimes, even the Vital prognosis of the case is severely influenced.

The therapeutic drug for vasospasm cerebral subsequent to arachnoid hemorrhage, the fasudil [hexahydro-1- (5-isoquinolinyl sulfonyl) -1H-1,4-diazepine] hydrochloride, is the only drug that is now used clinically (Japanese Kokai Tokkyo Koho S61-227581).

Apart from the mentioned drug, it is known that compounds that have an isoquinoline ring substituted by a cyclic aminosulfonyl in position 5 are useful as drugs cerebrovascular (vasodilators, circulation enhancers brain and metabolism, anti-angina drugs, drugs prophylactic and therapeutic for cerebrovascular thrombosis or cardiovascular and prophylactic and therapeutic drugs against hypertension) [Japanese Kokai Tokkyo Koho S57-156463, S58-121279, S61-227581, JP-A-61152658 and JP-A-2256617].

However, no compound is known that have an isoquinoline skeleton substituted by a group cyclic aminosulfonyl in position 5 and further substituted in position 4.

Description of the invention

The object of the invention is to provide a compound that is structurally new, low toxic level and superior in prophylactic or therapeutic effect to drugs and known for cerebrovascular diseases, especially in quality of cerebral vasospasm inhibitor.

To reach the mentioned object, the inventors of the present invention have synthesized and explored a large number of structurally new compounds and have found that a compound, which conforms to the following general formula [I], It has a very satisfactory activity in terms of investing cerebral vasospasm. The present invention has been developed on The basis of this finding.

The present invention further relates to a compound of the following general formula [I] or a salt pharmaceutically acceptable thereof or to a solvate thereof and to a pharmaceutical composition that contains it as a principle active

one

in the what

R1 means methyl or fluorine;

R2 means hydrogen, hydroxy or halogen;

R3 means hydrogen, alkyl C 1 -C 6 or amidino;

ring A means hexahydro-1H-1,4-diazepinyl, the atom or carbon atoms of the ring may be substituted by C 1 -C 6 alkyl.

In the chemical structure, the compound of the invention is characterized in that the position 4 of the skeleton Isoquinoline is substituted by a substituent chosen from methyl and fluorine

The present invention is now described in detail.

The term "alkyl" in the context of the The present invention comprises straight chain alkyl groups or branched from 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. Among them are preferred alkyl groups of 1 to 4 carbon atoms and is especially preferred The methyl

The term "halogen" includes chlorine, fluorine, bromine and iodine.

The ring hexahydro-1H-1,4-diazepinyl it may be substituted on one or more of its carbon atoms for a total of 1 to 4 alkyl substituents C_ {1} -C_ {6} same or different.

The salts of the compound [I] according to the invention include salts of inorganic acids, for example acid hydrochloric, sulfuric acid, nitric acid, phosphoric acid, acid hydrofluoric and hydrobromic acid and salts of organic acids, for example acetic acid, tartaric acid, lactic acid, acid citric, fumaric acid, maleic acid, succinic acid, acid methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, acid toluenesulfonic acid, naphthalenesulfonic acid and acid camphor sulfon.

The compound [I] of the invention can be obtained for example by the following procedure.

Process one

two

(where R 1, R 2, R 3 and the ring A have the meanings defined above; R 31 has the same meaning as R3 or means a protecting group; L1 means hydroxy or a group outgoing).

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The leaving group L1 comprises residues of reactive sulfonic acid derivatives mentioned above. The protecting group R31 comprises acyl groups, for example formyl, acetyl or benzoyl; aralkyloxycarbonyl, for example benzyloxycarbonyl; alkoxycarbonyl, for example tert-butoxycarbonyl; and aralkyl, for example benzyl

An amine of the formula is reacted general [III] with a sulfonic acid of the general formula [II] or a reactive derivative thereof, in an appropriate solvent and, if it were necessary, the protective group is removed to recover the compound [I]. The reaction solvent can be any solvent that does not interfere with the reaction, therefore it can be an ether, for example tetrahydrofuran, dioxane or diethyl ether; a hydrocarbon, for example benzene or toluene; a hydrocarbon halogenated, for example methylene chloride or chloroform; a aprotic solvent, for example the N, N-dimethylformamide or the N, N-dimethylacetamide; pyridine, acetonitrile, etc. or mixtures of said solvents. The reactive acid derivative sulfonic acid includes sulphonic acid halides (eg chloride of sulfonyl or sulfonyl bromide), sulfonic anhydride and N-sulfonylimidazolide, among others. It is preferred in especially a sulfonyl halide.

The reaction is preferably carried out in presence of a base. The base comprises various alkalis, for example alkali metal hydrogen carbonates (e.g. sodium hydrogen carbonate), alkali metal carbonates (e.g. potassium carbonate) and alkali metal hydroxides (e.g. sodium hydroxide or potassium hydroxide) and tertiary amines organic, for example triethylamine and triethylene diamine. When, as solvent of the reaction, a solvent is used basic, for example pyridine, then you don't need to use another base. Therefore it is advantageous to use a solvent of this kind.

The reaction is usually carried out at room temperature, but eventually it can be done by cooling or by heating, for example between -78 and 150 ° C, preferably between 0 and 120 ° C. When a base is used, the amount of reactive derivative [II] with respect to the amine [III] is preferably 1 to 10 molar equivalents and more preferably 1 to 3 equivalents molars The amount of base referred to the amine [III] is with preference of 1 to 10 molar equivalents and more preferably 1 to 3 molar equivalents. If the base is not used, then the amount of said reactive derivative [II] with respect to the amine [III] will be equimolar or less and will be preferably located in the range of 0.5 to 0.1 molar equivalents. Reaction time depends on the reagents used as starting compounds and the solvent used, reaction temperature and other conditions, but in general it is between 5 minutes and 70 hours. Yes if necessary, once the reaction is over, the group is removed protector by a known procedure.

Process two

3

(in which R 1, R 2, R 3, R 31 and Ring A has the meanings defined above; Y means oxygen, sulfur or SO_ {2}).

A compound of the general formula is treated [IV] with an acid or heated for aromatization and, if it were necessary, the protective group is removed to recover the compound [I]. The reaction can be carried out by a known method (J. Chem. Soc. C., 1971, 1227).

Process 3

4

(in which R 1, R 2, R 3, R 31, the ring A and Y have the meanings defined previously).

A compound of the formula [V] is treated with a acidic or heated for aromatization and, if necessary, it remove the protecting group to obtain the compound [I]. Is reaction is carried out by a known method (J. Chem. Soc. C., 1971, 1227).

Process 4

(The compound of the formula [I], in which R 2 is hydrogen and R 1 is a methyl group)

5

(where R 3 and ring A have the previous meanings; R 11 means a methyl group; R 10 means halogen).

The halogen R 10 is preferably chlorine or bromine.

A halide of the general formula [Ia] is treated with an organometallic reagent equivalent to R 11, for example a Grignard or methyl lithium reagent, to obtain the compound [Ig] (compound of the formula [I], in which R2 is hydrogen and R1 is a methyl substituent). This reaction can be carried out by a known method (EP-A-429 341).

The compound [Ib] can also be obtained in the that ring A means a cyclic amino group not linked by link, by the following method.

Process 5

(Formula [I], where ring A is an amino group cyclic not linked with link)

6

(in which R 1, R 2 and R 3 A have the meanings defined above; G means alkylene C 3 and Q means C 2 alkylene; said alkylene groups they can have 1 to 4 identical or different substituents, chosen among the substituents mentioned for ring a in any replaceable position; the group cyclic

7

which is formed by reaction of compound [VI] with compound [IX] means 8 wherein ring A 'means a cyclic amino group not linked by link; L2 means a leaving group).

The leaving group L2 comprises halogen, by example chlorine or bromine, and acyloxy, for example acetyloxy, mesyloxy or tosyloxy.

Compound [VI] (a halide or a reactive derivative) with the compound [IX] (the amine, guanidine or ammonium corresponding to R3) to obtain the compound [Ib]. This reaction can be carried out by a known method (Minutes Chemica Scand., 1991, 45, 621).

Process 6

9

(in which R 1, R 2, R 3, R 31, L2, G and Q have the meanings defined previously).

Compound [XI] (a halide or a reactive derivative) with the compound [VII] and, if necessary, the protective group is removed with an acid or an alkali to get the compound [Ib]. This reaction can be carried out by a known method (Acta Chemica Scand., 1991, 45, 621).

Process 7

10

eleven

12

(in which R 1, R 2, R 3, R 31, ring A ', G, Q, L 1 and L 2 have the meanings defined previously).

Stage one

The aminoalkylalcohol of the formula [XII] with compound [II] in a manner similar to process 1 to obtain the compound [VIIIa].

Stage two

Through a procedure known per se convert the hydroxyl group of compound [VIIIa] into halogen (eg Cl, Br) or acyloxy (eg tosyloxy, methanesulfonyloxy, acetyloxy) to obtain the compound [VIIIb].

Stage 3

Compound is reacted [VIIIb] is made react with the aminoalkylalcohol [XIII] in a solvent appropriate, in the absence or in the presence of a base, in a method by the rest similar to process 1 to obtain the compound [VIIIc].

Stage 4

The secondary amino group of the composed [VIIIc] by a process known per se for obtain the compound [VIIId]. The protecting group can be one any of the protection groups mentioned for the process one.

Stage 5

The compound is usually converted [VIIId] in the compound [VIIIe].

Stage 6

Compound [VIIIe] is treated with a base in a appropriate solvent and, if necessary, is then treated with a acid or with an alkali to remove the protective group, obtaining thus the compound [Ib]. The base that can be used It comprises several alkalis, for example sodium hydride, the sodium hydrogen carbonate, potassium carbonate, hydroxide sodium and potassium hydroxide and organic tertiary amines, by example triethylamine or triethylene diamine. This reaction is carried out using the same solvent and the same conditions which were used in process 1.

The compound [Ib] can be obtained by subjecting the compound [VIIId] to an intramolecular dehydration reaction using triphenylphosphine and diethyl azodicarboxylate and eliminating the protective group

The compound of the formula [I] in which R1 it is alkyl and R2 is hydroxy or halogen can be obtained by oxidation of compound [Id] (formula [I] in which R1 is alkyl and R2 is hydrogen), obtained according to one any of the processes described above. Therefore the compound in which R2 is hydroxy can be obtained by heating the compound [Id] together with an oxidant, for example peroxide of hydrogen, a tert-butyl peroxide or peroxide, in a solvent, for example acetic acid, methylene chloride or chloroform, to obtain the isoquinoline N-oxide and hydrolyzing the latter with acetic anhydride by heating. Further, heating said isoquinoline N-oxide together with oxychloride of phosphorus or phosphorus tribromide the compound can be obtained in the that R2 is halogen.

The compound [I] having a substituent on the ring nitrogen atom hexahydro-1H-1,4-diazepinyl, that is, the compound [Ie] (of the formula [I], R 3 means a C1-C6 alkyl or amidino) group can also obtained by introducing a substituent group in the compound [If] (in the formula [I], R 3 means hydrogen) obtained by any one of the processes described above. For example, the compound in which R3 means alkyl C 1 -C 6 can be obtained by reacting the compound [If] with an alkylating agent in the presence of a base. The compound in which R 3 is amidino can be obtained by reaction of the compound [If] with an isourea derivative in the presence of a base. The base that can be used in this case can be an alkali, for example sodium hydrogen carbonate, potassium carbonate, hydroxide sodium and potassium hydroxide, or organic tertiary amines, by example triethylamine, etc. The solvent that can be used in the reaction includes but is not limited to ethanol, methanol, benzene, toluene, N, N-dimethylformamide and sulfoxide of dimethyl. Therefore, the compound in which R 3 is amidino can be obtained by reacting the compound [If] with S-methylisothiourea or O-methylisourea in a solvent (eg tetrahydrofuran, ethanol or methanol) to room temperature or by heating.

In the previous procurement processes, the hydroxyl and amino groups can be protected, if necessary, with suitable known protective groups and, once the contemplated reaction, deprotected by procedures per se known, for example an acid treatment, treatment with alkali or catalytic reduction. The amino protecting group that can be used includes but is not limited to benzyl, benzyloxycarbonyl and trifluoroacetyl. The hydroxy protecting group which can be used includes but is not limited to methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl, tert-butyl, benzyl, trimethylsilyl and tert-butyldimethylsilyl. When he hydroxy group is protected with benzyl, catalytic reduction produces a simultaneous debenzylation regenerating the hydroxyl group free.

The starting compound [II] can be obtained by the procedure described in reference example 1.

The starting compound [III] can be purchased from a commercial provider or obtained by the procedure described in reference example 2.

The starting compounds [IV] and [V] can Obtained by the method described in J. Chem. Soc. C., 1971, 1227

The starting compounds [VI] and [VII] can Obtained according to the procedures described in Acta Chemica Scand., 1991, 45, 621.

The starting compounds [IX] and [XI] can acquired from commercial suppliers.

The starting compounds [XII] and [XIII] can also purchased from commercial suppliers.

Since the compound [I] in which R2 means hydroxy can exist in the following tautomeric forms, both isomers are included within the scope of the invention.

13

Some forms of the compound [I] of the invention they can have asymmetric carbon atoms and, as such, each of these can be presented in the form of optical isomers. Such isomers and mixtures thereof are also included within the scope of the invention. Normally you get a modification racemic The racemic modification as such is pharmacologically active, while each racemic modification can be resolved possibly in the isomeric components. Such mixture of isomers can be fractionated to obtain the respective isomers by known optical resolution techniques, for example the technique that consists in reacting the racemic modification with an acid optically active carboxylic acid (eg acid (+) - or (-) - tartaric acid or (+) - or (-) - malic) or with sulphonic acid (eg acid (+) - camphor sulfon) to obtain a salt and isolate salt by fractional crystallization or the technique that consists of Use a chiral column. The optical isomers can be obtained also using optically active forms of the compounds of heading [III], [IV], [V], [VI], [VII], [XII], [XIII] or [Ia] (configuration S or configuration R).

The salt of the compound [I] of the present invention It can be obtained by a method known per se. For example, him hydrochloride of example [I] can be obtained by dissolving the compound [I] in a solution of hydrogen chloride in alcohol or ether ethyl.

Recrystallization of compound [I] or a salt thereof in an appropriate solvent (including water) can give rise to the corresponding solvate (including hydrate). Such Solvates are also included within the scope of the invention. For example, the hydrate of the compound [I] according to the invention can formed by recrystallization of compound [I] in alcohol aqueous.

The compound of the invention may have polymorphism. Polymorphic forms are also included. within the scope of the invention.

The compound of the invention produced by the method described above can be isolated and purified in the form free base or acid addition salt by procedures yes known, for example by concentration, pH adjustment, redistribution, solvent extraction, crystallization, fractional distillation and chromatography.

The compound of the invention has activity of inhibition of cerebral vasospasms and, as such, can be used with advantage in disease prevention and treatment cerebrovascular, especially brain tissue disorders due to cerebral vasospasm after hemorrhage cerebral.

For use as a medicine, the compound of the invention can be administered either as is, either in the form of a drug composition that contains it in a proportion of the 0.1 to 99.5%, preferably 0.5 to 90%, in an excipient Pharmaceutically acceptable, non-toxic and inert, to animals Mammals, including human people.

As an excipient or fresh vehicle mentioned one or several components chosen from among solid, semi-solid or liquid diluents, filler charges and other formulation additives. The drug composition is preferably administered in unit dosage forms. The Pharmaceutical composition of the invention can be administered via oral, parenteral, local (eg transdermal) or rectal. How is it natural, the appropriate dosage form will be chosen for each of the routes of administration. Among the forms of administration just mentioned, intravenous and oral.

The dose will be adjusted with preference to patient factors, such as age and body weight, the pathway of administration and the nature and severity of the disease. For the use of prophylactic or therapeutic drug for vasospasm brain in adult patients, the daily intravenous dose of active substance can be between 0.1 and 100 mg / patient, with preference between 1 and 30 mg / patient. In case of administration orally, the daily dose can be between 1 and 1,000 mg / patient, preferably between 1 and 30 mg / patient. The two lowest can be sufficient in certain cases, while higher doses They may be necessary for other cases. In addition, the daily dose It can be divided and administered in several smaller doses.

Oral administration can be done using a solid or liquid unit dosage form, for example bulk powders, powders, tablets, dragees, capsules, granules, suspension, solution, syrup, drops, sublingual tablets, etc.

Bulk powders can be obtained by crushing the compound of the invention up to a particle size (diameter) suitable. Powders can be made by crushing the compound until a suitable particle diameter and mixing the resulting powder with a pharmaceutical excipient, for example with a carbohydrate edible, for example starch or handyman, which can be crushed also previously similarly. If necessary, the powders resulting can be complemented with a flavoring, a preservative, a dispersant, a dye, a perfume and / or others additives

The capsules can be manufactured by packaging said bulk powders or powders previously prepared in capsules of jelly or other, or by packing the granules in them manufactured by the procedure described below for tablets Lubricants and / or fluidizers, for example silica colloidal, talc, magnesium stearate, calcium stearate and solid polyethylene glycol, can be added in finely form divided before the packaging operation just described. They can disintegrants and solubilizers are added, for example the carboxymethyl cellulose, calcium carboxymethyl cellulose, low-grade hydroxypropylcellulose, croscarmellose sodium, sodium carboxymethyl starch, calcium carbonate and sodium carbonate, in which case the efficacy of the drug after Ingestion of the capsules may be extended.

The finely divided compound of the invention can be suspended and dispersed in vegetable oil, in polyethylene glycol, in glycerin or in a surfactant and packaged in Gelatin capsules, in this way soft capsules are obtained. The tablets can be made by preparing a powdery mixture of composed with an excipient, processing them in granules or tablets, adding a disintegrant and / or a lubricant and Compressing the mixture The powder mixture can be prepared by mixing powdered powders of the active component with any of the diluents and bases mentioned. If i were binders may also be added (eg. sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, gelatin, polyvinylpyrrolidone, alcohol polyvinyl, etc.), dissolution retardants (eg paraffin), reabsorption agents (eg quaternary salts) and / or absorbents (eg bentonite, kaolin, dicalcium phosphate, etc.). Mix powdery can become granules by moisturizing it with a binder, for example a syrup, a paste of starch, gum Arabic, a solution of cellulose or a solution of a polymer, shaking the wetted powder well, drying it and spraying it. In instead of converting the powders into granules as above, the powders can be compressed in a tablet making machine and the resulting raw tablets can be crushed into granules. The granules thus obtained can be protected against agglomeration adding a lubricant, for example stearic acid, a salt of stearic acid, talc or mineral oil. The lubricated composition this way it can be pressed next. Core tablets resulting can be coated with a film forming agent or with agent of sugar cover.

Alternatively, the active substance can mix directly with an inert excipient of good fluidity, without undergoing granulation or pressing procedure mentioned above and the mixture can become directly in tablets. A cover can also be applied transparent or translucent protective, capable of providing a airtight varnish or other film, a sugar cover, a polymer cover or a glazed wax cover, for example. Other dosage forms for oral administration, by example solutions, syrups and elixirs can also be presented in unit dosage forms containing in each case a predetermined amount of the drug. The syrups are manufactured dissolving the active substance in a flavored aqueous medium ideal, while elixirs are manufactured using a vehicle non-toxic alcoholic The suspensions are manufactured by dispersing the active substance in non-toxic vehicles. When necessary solubilizers and emulsifiers can also be added (eg. ethoxylated isostearyl alcohol, polyethoxylated sorbite esters, etc.) as well as preservatives and flavorings (eg peppermint essence, saccharin, etc.).

If necessary, dose formulations Unitary for oral administration can be microencapsulated. Such formulations can be coated with or included in a matrix or polymer or wax structure to prolong the effect or to Get a persistent release.

Parenteral administration can lead to out using liquid unit dosage forms, e.g. solutions or suspensions for subcutaneous injection, intramuscular or intravenous. Such dosage forms can be manufactured by suspending or dissolving a predetermined amount of the active substance in a non-toxic injectable liquid vehicle, eg in an aqueous medium or an oily medium, and sterilizing the suspension or resulting solution. To achieve an injection Isotonic is added a non-toxic salt or a solution thereof. Stabilizers, preservatives, emulsifiers can also be used. and other additives.

Rectal administration can be performed. using suppositories manufactured by dissolution or suspension of active substance in a solid medium of low melting point, soluble in water or insoluble, eg polyethylene glycol, cocoa butter, a semisynthetic oil base (eg Witepsol ™), an ester of higher fatty acids (eg myristyl palmitate) or a mixture of the above.

The best embodiment of the invention

The following reference examples, relative to obtain the representative starting compounds, the working examples related to obtaining the compounds of the invention and the formulations and test examples of the Representative compounds of the invention are presented by title. illustrative of the invention and should not be taken as designed to Define or restrict the scope of the invention. It is understood that the Specific rotation is measured at 20 ° C.

Reference Example one

5-chlorosulfonyl-4-methylisoquinoline (one) 4-methyl-5-nitroisoquinoline

45 ml of concentrated sulfuric acid is added add 12.75 g of 4-methylisoquinoline (obtained with arrangement to Tetrahedron 38, 3347, 1982) cooling with ice and then it is added by dripping at a temperature that does not exceed 0ºC a solution of 9.02 g of potassium nitrate in 34 ml of sulfuric acid concentrated. The reaction mixture is stirred for 30 minutes, pour over ice-water containing aqueous ammonia and extracted with ethyl acetate. The extract is dried with sulfate anhydrous magnesium and the solvent is removed by distillation at reduced pressure The residue is purified by chromatography of column through silica gel (hexane / ethyl acetate = 1/1), obtaining 12.0 g of slightly yellow crystals.

(two) 5-Amino-4-methylisoquinoline

To 120 ml of a solution prepared by dissolving 12.0 g of 4-methyl-5-nitroisoquinoline obtained in (1) in methanol 0.73 g of platinum oxide are added and a catalytic reduction is carried out at 25 ° C for 2 hours with a stream of hydrogen at a pressure of 1 atmosphere. Is filtered this reaction mixture and the filtered liquid is concentrated. I know Purify the residue by column chromatography through gel silica (chloroform / acetone = 9/1), obtaining 9.12 g of crystals slightly brown

(3) 5-Chlorosulfonyl-4-methylisoquinoline

At a suspension of 11.5 g of 5-amino-4-methylisoquinoline obtained in a manner similar to that described in (2) in hydrochloric acid concentrate is added drip at -5 ° C 36 ml of a solution 7.2 g aqueous of sodium nitrite and the mixture is stirred for 1 time. This reaction mixture is poured at a temperature drip ambient over a mixture of 200 ml of saturated acetic acid with Sulfur dioxide gas and 4.1 g of hydrated cupric chloride. I know Stir the reaction mixture for 1 hour, concentrate, Basify with sodium hydrogen carbonate and extract with chloroform. The extract is dried and concentrated and the crystals are recrystallized crude resulting in benzene, obtaining 8.1 g of the compound desired (slightly yellow crystals), m.p. 113-118 ° C.

Reference Example two

(S) -hexahydro-2-methyl-1H-1,4-diazepine hydrobromide (one) (S) -3- [N- (t-butoxycarbonyl) -N- [2- (N-p-toluenesulfonyl) aminopropyl] amino] -1-propanol

It N, O-ditosila the L-alaninol in the usual way and the rest O-tosyl of the resulting compound is subjected to a replacement reaction with the 3-amino-1-propanol. Thus 17.7 g of tosyl chloride are added to a solution of 3.2 g of L-alaninol in 50 ml of pyridine cooling with ice and stir the mixture at room temperature for 3 days. The reaction mixture is concentrated and the residue is diluted with ether, wash with 1N hydrochloric acid and water, dry and dry concentrate. The residue is dissolved in 150 ml of tetrahydrofuran, add 3-aminopropanol ice cooling and Stir the mixture at room temperature for 1.5 hours. Later concentrate the reaction mixture and chloroform is added to the residue. This mixture is washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of chloride sodium, dried and concentrated. The residue is purified by silica gel column chromatography (chloride methylene / methanol / aqueous ammonia = 8/1 / 0.1), obtaining 10.2 g of the (S) -3- [N- [2- [N - [(p-toluene) sulfonyl] amino] propyl] amino] -1-propanol  (brown oil). 10.2 g of this compound are dissolved in 90 ml of dioxane-water (2: 1) and cooling with ice are added 50 ml of a 1N aqueous solution of sodium hydroxide and 11.6 g of di-tert-butyl dicarbonate, then it is stirred at room temperature overnight. I know concentrate this reaction mixture, dilute with chloroform and water, it is neutralized with a 5% potassium hydrogen sulfate solution in water and extracted with chloroform. The extract is dried, filtered and dried. distil the filtered liquid under reduced pressure, obtaining 13.7 g from (S) -3- [N- (tert-butoxycarbonyl) -N- [2- [N- (p-toluene) sulfonyl] amino] propyl] amino] -1-propanol (slightly yellow oil). This oil is subjected to the reaction Next without purifying.

(two) (S) - (-) - hexahydro-2-methyl-1H-1,4-diazepine hydrobromide

To a solution of 13.7 g of the compound obtained in (1) in tetrahydrofuran are added triphenylphosphine and diethyl azodicarboxylate (40% in toluene) in boluses and stirred the mixture for 20 minutes by heating in a dryer. The reaction mixture and the residue is purified by chromatography of column through silica gel (n-hexane / acetate of ethyl = 3/1), obtaining 13.1 g of a colorless oil. I know dissolve the oil in 180 ml of 30% hydrogen bromide in acid acetic and the mixture is stirred at room temperature for 30 minutes Then 13.4 g of phenol are added and the Stirring the mixture at 60 ° C for 7 hours. The reaction mixture, a small amount of ethanol and the resulting crystalline mass is collected by filtration and dry, obtaining 6.44 g of (S) - (-) - hexahydro-2-methyl-1H-1,4-diazepine hydrobromide (white crystals).

[α] D: -13.60 ° (c = 1.12, H2O).

Reference Example 3

2,7-dimethyl-hexahydro-1H-1,4-diazepine hydrobromide

Starting from 3-aminobutan-1-ol in place of D-alaninol the procedure of the reference example 2, obtaining the epigraph compound.

Example one

Hexahydro-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine dihydrochloride

(1) To 30 ml of a solution obtained by dissolving 1 g of 1- (tert-butoxycarbonyl) hexahydro-1H-1,4-diazepine and 0.97 g of triethylamine in chloroform are added by cooling with ice 1 g of 5-chlorosulfonyl-4-methylisoquinoline and stir the mixture for 18 hours. The mixture is poured ice-water reactant and extracted with chloroform. The extract is dried and concentrated and the resulting oil by column chromatography through gel silica, obtaining 1.38 g of an oil. This oil dissolves in 30 ml of ethanol, then 20 ml of 1N hydrochloric acid are added and the mixture is boiled at reflux for 1 hour. I know the reaction mixture is concentrated and the residue is basified and extract with chloroform. It is dried, the solvent is distilled to obtain 0.72 g of white crystals.

(2) The above crystals dissolve in chloroform and ethanol saturated with hydrogen chloride is added. The mixture is concentrated and the white crystals are collected. resulting, obtaining the desired compound (0.8 g).

Elementary Analysis (of C 15 H 19 N 3 O 2 \ 2dCl2HCl \ O2)

calculated (%): C 45.42 H 5.80 N 10.61 found (%): C 45.82 H 5.69 N 10.56

IR spectrum (KBr), nu (cm -1): 3300, 1639, 1615, 1472, 1333, 1146, 764.

Example two

Hexahydro-4 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine-1-carboximidamide dihydrochloride

The benzyloxycarbonylate sulfate is S-methylisothiourea in the usual way (Jikken Kagaku Koza [Experimental Chemistry Series] 22, Yuki Gosei (Organic Synthesis), edition IV, 228, 1992) and then reacted with 4 molar equivalents of homopiperazine in tetrahydrofuran for get the hexahydro-1H-1,4-diazepine-1-carboximidamide. Starting from 0.68 g of this compound and 0.5 g of 5-chlorosulfonyl-4-methylisoquinoline the reaction procedure of example 1 is repeated to obtain 0.16 g of the compound sought in the form of white crystals.

Elementary Analysis (of C 16 H 21 N 5 O 2 S 2 HCl 2 O 2 O)

calculated (%): C 42.07 H 5.92 N 15.34 found (%): C 42.73 H 5.46 N 15.27

IR spectrum (KBr), nu (cm -1): 3300, 1653, 1607, 1327, 1148, 569.

Example 3

Hexahydro-1 - [(1-hydroxy-4-methyl-5-isoquinolinyl) -sulfonyl] -1H-1,4-diazepine  hydrochloride

30 ml of a suspension prepared by suspending 2.25 g of hexahydro-1 - [(4-methyl-4-isoquinolinyl) sulfonyl] -1H-1,4-diazepine in pyridine, 2.0 g of acetic anhydride are added and the mixture is stirred mix at 60 ° C for 30 minutes. This mixture is concentrated reactant, it is basified with sodium hydrogen carbonate / H2O and It is extracted with chloroform. The extract is dried and concentrated, obtaining 1.91 g of 1-acetyl-hexahydro-4 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine in the form of oil.

1.91 g of the above compound is dissolved in 30 ml of acetic acid and 0.94 g of added to room temperature 30% hydrogen peroxide in water and the mixture is stirred at 70 ° C for 16 hours This reaction mixture was poured onto water and basify with potassium carbonate and crystalline mass is collected resulting by filtration, obtaining 1.87 g of 5- (4-Acetyl-hexahydro-1H-1,4-diazepin-1-yl) sulfonyl-4-methylisoquinoline-2-oxide in the form of white crystals.

A solution is prepared by dissolving 1.87 g of the previous compound in 40 ml acetic anhydride, is maintained in Boil at reflux for 4 hours and then concentrate. I know dissolve the residue in 20 ml of methanol and after adding 10 ml of 2N sodium hydroxide in H2O the mixture is stirred at 60 ° C for 5 minutes. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with chloroform. Dries on extract and concentrate and the residue is purified by chromatography column through silica gel (chloroform / methanol = 17/1), obtaining 1.15 g of 1-acetyl-hexahydro-4 - [(1-hydroxy-4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine. A suspension of this compound in 1N hydrochloric acid is maintained boil at reflux for 11 hours and then concentrate. I know Purify the residue by column chromatography through gel silica (chloroform / methanol = 4/1) and is treated as described in the Example 1 (1), to obtain 0.477 g of the compound sought in form of white crystals.

Elementary Analysis (of C 15 H 19 N 3 O 3 S \ HCl)

calculated (%): C 50.34 H 5.63 N 11.74 found (%): C 49.80 H 5.57 N 11.37

IR spectrum (KBr), nu (cm -1): 1636, 1593, 1323, 1146, 1011, 762, 596.

Example 4

(S) - (+) - Hexahydro-2-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine hydrochloride

To a suspension prepared by suspending 24.0 g (S) -hexahydro-2-methyl-1H-1,4-diazepine hydrobromide obtained in reference example 2 in 40 ml of tetrahydrofuran are added by cooling with ice 1.16 g of sodium hydroxide and 20 ml of 0.1 N sodium hydroxide in H2O. TO then 1.58 g of dicarbonate of drip are added di-tert-butyl and the mixture is stirred at room temperature overnight. The mixture is concentrated. reactant and extracted with chloroform. The extract is dried and concentrate and purify the residue by column chromatography a through silica gel (chloroform / methanol = 10/1), obtaining 1.5 g of a colorless oil. This product is reacted then with 2.50 g of 5-chlorosulfonyl-4-methylisoquinoline in the manner indicated in example 1, obtaining 0.53 g of the compound wanted (white crystals). m.p. 146-150 ° C.

Elementary Analysis (of C 16 H 21 N 3 O 2 S \ HCl \ H 2 O)

calculated (%): C 51.40 H 6.47 N 11.24 found (%): C 51.40 H 6.68 N 11.26

[α] D: + 16.05 ° (c = 1.07, H2O).

Example 5

1 - [(4-fluor-5-isoquinolinyl) sulfonyl] -hexahydro-1H-1,4-diazepine dihydrochloride

Starting from 25 g of 4-bromoisoquinoline (synthesized according to J. Am. Chem. Soc. 64 , 783, 1942 and 73 , 687, 1951), 4-fluorisoquinoline is obtained. Starting from 5.87 g of this compound, 5-chlorosulfonyl-4-fluorisoquinoline is synthesized by the same procedure described in reference example 1. 1.0 g of the compound obtained is reacted with 1.6 g of 1- (tert-butoxycarbonyl) -hexahydro-1H-1,4-diazepine. The reaction mixture is then treated in the manner described in Example 1, obtaining 1.40 g of the desired compound (white crystals). mp 255-260 ° C (decomp.).

Elementary Analysis (of C 14 H 16 FN 3 O 2 S 2 HCl)

calculated (%): C 43.99 H 4.75 N 10.99 found (%): C 43.72 H 4.68 N 10.85

Example 6

Hexahydro-7-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine  dihydrochloride

Starting from 0.64 g of 1- (tert-butoxycarbonyl) hexahydro-5-methyl-1H-1, 4-diazepine, prepared by protecting position 1 of the hexahydro-5-methyl-1H-1,4-diazepine, synthesized according to US-3 040 029, and otherwise repeating the procedure of example 1 are obtained 0.27 g of the desired compound (white crystals).

m.p. 270-275 ° C (decomp.).

Elementary Analysis (of C 16 H 21 N 3 O 2 S 2 HCl)

calculated (%): C 48.98 H 5.91 N 10.71 found (%): C 48.84 H 6.14 N 10.63

Example 7

Hexahydro-6-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine  dihydrochloride

Starting from 0.64 g of the hexahydro-6-methyl-1H-1,4-diazepine, synthesized according to US-3 040 029, and by repeating otherwise the procedure of example 1 are obtained 0.79 g of the desired compound (white crystals).

m.p. 264-271 ° C (decomp.).

Elementary Analysis (of C 16 H 21 N 3 O 2 S 2 HCl)

calculated (%): C 48.98 H 5.91 N 10.71 found (%): C 48.98 H 6.02 N 10.72

Example 8

Hexahydro-5-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine  dihydrochloride

Starting from 0.29 g of the hexahydro-5-methyl-1H-1,4-diazepine, synthesized according to US-3 040 029, and 0.48 g of the 5-chlorosulfonyl-4-methylisoquinoline and by repeating otherwise the procedure of example 1 are obtained 0.3 g of the desired compound (white crystals).

m.p. 271-274 ° C (decomp.).

Elementary Analysis (of C 16 H 21 N 3 O 2 S 2 HCl)

calculated (%): C 48.98 H 5.91 N 10.71 found (%): C 48.83 H 6.11 N 10.46

Example 9

Hexahydro-2-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine  dihydrochloride

Starting from 1.07 g of 4- (tert-butoxycarbonyl) -hexahydro-2-methyl-1H-1,4-diazepine, prepared protecting position 4 of hexahydro-2-methyl-1H-1,4-diazepine (2.8 g), synthesized according to J. Med. Chem. 33 , 142, 1990 and 1.21 g of the 5-chlorosulfonyl-4-methylisoquinoline and by repeating the procedure of Example 1 otherwise, 0 are obtained, 27 g of the desired compound (white crystals).

m.p. 156-162 ° C (decomp.).

Elementary Analysis (of C 16 H 21 N 3 O 2 S \ HCl)

calculated (%): C 54.00 H 6.23 N 11.81 found (%): C 53.89 H 6.38 N 11.64

Example 10

(R) - (-) - Hexahydro-2-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine hydrochloride

Process one

Starting from 15.0 g of D-alaninol the procedures of reference example 2 and the Example 4 to obtain 1.42 g of the desired compound (crystals white).

m.p. 146-150 ° C.

Elementary Analysis (of C 16 H 21 N 3 O 2 S \ HCl \ cdot3 / 2H 2 O)

calculated (%): C 50.19 H 6.58 N 10.97 found (%): C 50.15 H 6.55 N 10.82

[α] D: -18.05 ° (c = 1.14, H2O).

Process two

(1) To a solution of 1.0 g of D-Alanine in 50 ml of methylene chloride add 2.02 g of triethylamine and then add by cooling with ice 3.22 g of 5-chlorosulfonyl-4-methylisoquinoline and stir the mixture for 2 hours. The mixture is diluted reactant with water and extracted with methylene chloride, dried Extract and concentrate. The residue is purified by chromatography column through silica gel (chloroform / methanol = 30/1), obtaining 3.0 g of (R) -2 - [(4-methyl-5-isoquinolinyl) sulfonylamino] -1-propanol (white crystals).

(2) To a solution of 1.1 g of the compound obtained in (1) in 8 ml of pyridine, 0.82 g of chloride is added of p-toluenesulfonyl and the mixture is stirred for one night. Then the pyridine is removed by distillation and dilute the residue with water, extract with chloroform, dry and dry concentrate. The residue is dissolved in 8 ml of tetrahydrofuran, then 0.80 g of 3-amino-1-propanol and The mixture is stirred at room temperature for 3 hours. I know remove the solvent by distillation and the residue is purified by silica gel column chromatography (chloroform / methanol / aqueous ammonia = 90/10/1), obtaining 1.3 g from (R) -3- [N- [2 - [[(4-methyl-5-isoquinolinyl) sulfonyl] amino] propyl] amino] -1-propanol (slightly yellow oil).

(3) To a solution of 5.8 g of the compound obtained in (2) in 60 ml of tetrahydrofuran 50 ml of a 0.1 N aqueous solution of sodium hydroxide. Chilling with ice a solution of 3.75 g of dicarbonate of di-tert-butyl in 40 ml of tetrahydrofuran and the mixture is stirred for 2 hours. The solvent by distillation, the residue is extracted with chloroform, Dry and concentrate. The residue is purified by chromatography of column through silica gel (chloroform / methanol = 20/1), obtaining 7.34 g of (R) -3- [N- (tert-butoxycarbonyl) -N- [2 - [[(4-methyl-5-isoquinolinyl) sulfonyl] amino] propyl] amino] -1-propanol (slightly yellow oil).

(4) To a solution of 1.8 g of the compound obtained in (3) in 30 ml of dry tetrahydrofuran, 1.62 is added g of triphenylphosphine and 1.07 g of diethyl azodicarboxylate and heat the mixture for 20 minutes. The mixture is concentrated. reactant and the residue is dissolved in 30 ml of chloride methylene To the resulting solution are added by cooling with ice 10 ml of trifluoroacetic acid and the mixture is stirred at temperature atmosphere for 1 hour. This reaction mixture is basified with a saturated solution of sodium hydrogen carbonate in H2O, is Extract with methylene chloride, dry and concentrate. It is purified the residue by column chromatography through silica gel (chloroform / methanol = 50/1) and becomes the hydrochloride of mode described in example 1 (2), obtaining 0.9 g of the compound wanted (white crystals).

m.p. 146-150 ° C.

Elementary Analysis (of C 16 H 21 N 3 O 2 S \ HCl \ C 2 O 2 O)

calculated (%): C 49.03 H 6.69 N 10.72 found (%): C 48.70 H 6.69 N 10.80

[α] D: -17.50 ° (c = 1.11, H2O).

Example eleven

2-Ethyl-hexahydro-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine  hydrochloride

Starting from 0.68 g of 1- (tert-butoxycarbonyl) -3-ethyl-hexahydro-1H-1,4-diazepine and 0.72 g of 5-chlorosulfonyl-4-methylisoquinoline and repeating otherwise the procedure described in example 1 0.38 g of the desired compound (white crystals) are obtained.

m.p. 208-210 ° C (decomp.).

Elementary Analysis (of C 17 H 23 N 3 O 2 S \ HCl)

calculated (%): C 55.20 H 6.54 N 11.36 found (%): C 55.30 H 6.83 N 11.08

Example 12

5,7-dimethyl-hexahydro-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine  hydrochloride

Starting from 0.77 g of 5,7-dimethyl-hexahydro-1H-1,4-diazepine and 0.48 g of 5-chlorosulfonyl-4-methylisoquinoline and repeating otherwise the procedure described in example 1 0.50 g of the desired compound (white crystals) are obtained.

m.p. 280-282 ° C (decomp.).

Elementary Analysis (of C 17 H 23 N 3 O 2 S \ HCl)

calculated (%): C 55.20 H 6.54 N 11.36 found (%): C 54.96 H 6.44 N 11.10

Example 13

(R) - (-) - hexahydro-1 - [(1-hydroxy-4-methyl-5-isoquinolinyl) sulfonyl] -2-methyl-1H-1,4-diazepine hydrochloride

Starting from 1.76 g of (R) - (-) - hexahydro-2-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine and repeating otherwise the procedure described in example 3, 0.65 g of the desired compound are obtained (colored crystals pale yellow).

m.p. 232-235 ° C (decomp.).

Elementary Analysis (of C 16 H 21 N 3 O 3 S \ HCl \ 1 / 4H 2 O)

calculated (%): C 51.06 H 6.03 N 11.16 found (%): C 51.17 H 6.08 N 11.04

[α] D: -32.14 ° (c = 1.04, H2O).

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Example 14

(S) - (+) - hexahydro-1 - [(1-hydroxy-4-methyl-5-isoquinolinyl) sulfonyl] -7-methyl-1H-1,4-diazepine hydrochloride

Starting from 1.06 g of (S) - (+) - hexahydro-7-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine and repeating otherwise the procedure described in example 3, 0.30 g of the desired compound (white crystals) are obtained.

m.p. 215-218 ° C (decomp.).

Elementary Analysis (of C 16 H 21 N 3 O 3 S \ HCl \ 3 D 2 O)

calculated (%): C 45.12 H 6.63 N 9.87 found (%): C 45.25 H 6.30 N 9.52

[α] D: + 26.66 ° (c = 1.13, H2O).

Example fifteen

3,5-dimethyl-hexahydro-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine hydrochloride

To a suspension of 1.5 g of 2,7-dimethyl-hexahydro-1H-1,4-diazepine  hydrobromide, obtained according to reference example 3, in ml of pyridine 1.58 g of 1,8-diazabicyclo [5.4.0] -7-undecene and after adding 0.84 g of 5-Chlorosulfonyl-4-methyl-isoquinoline The mixture is stirred at room temperature for 1 hour. I know The reaction mixture is concentrated and the residue is diluted with water. Extract with chloroform, dry and concentrate. The residue by column chromatography through silica gel (chloroform / methanol = 30/1) and becomes the hydrochloride of usual way, obtaining 0.70 of the desired compound (crystals white).

m.p. 287-290 ° C (decomp.).

Elementary Analysis (of C 17 H 23 N 3 O 2 S \ HCl \ 1 / 2H 2 O)

calculated (%): C 53.89 H 6.65 N 11.09 found (%): C 53.79 H 6.47 N 11.35

Example 16

Hexahydro-3-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine  hydrochloride

Starting from 0.72 g of hexahydro-2-methyl-1H-1,4-diazepine hydrobromide, synthesized in the manner described in example 4, and otherwise repeating the procedure of example 15 are obtained 0.53 g of the desired compound (white crystals).

m.p. 290-294 ° C (decomp.).

Elementary Analysis (of C 16 H 21 N 3 O 2 S \ HCl \ H 2 O)

calculated (%): C 51.40 H 6.47 N 11.23 found (%): C 51.98 H 6.95 N 11.18

Example 17

(S) - (-) - hexahydro-7-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl-1H-1,4-diazepine hydrochloride

Starting from 2.0 g of 3- (S) -aminobutan-1-ol (synthesized according to J. Org. Chem. 42, 1650, 1977) instead of D-alaninol and 2-aminoethanol in place of 3-amino-1-propanol and otherwise repeating the procedure described in example 10, process 2, 1.10 g of the desired compound are obtained (crystals white).

m.p. 282-285 ° C.

Elementary Analysis (of C 16 H 21 N 3 O 2 S \ HCl \ cdot1 / 2H 2 O)

calculated (%): C 52.67 H 6.35 N 11.52 found (%): C 52.79 H 6.19 N 11.51

[α] D: -1.74 ° (c = 1.03, H2O).

Example 18

(R) - (+) - hexahydro-7-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl-1H-1,4-diazepine hydrochloride

Starting from 2.0 g of 3- (R) -aminobutan-1-ol (synthesized according to J. Org. Chem. 42, 1650, 1977) instead of D-alaninol and 2-aminoethanol in place of 3-amino-1-propanol and otherwise repeating the procedure described in example 10, process 2, 1.20 g of the desired compound are obtained (crystals white).

m.p. 278-282 ° C (decomp.).

Elementary Analysis (of C 16 H 21 N 3 O 2 S \ HCl \ cdot3 / 2H 2 O)

calculated (%): C 50.19 H 6.58 N 10.97 found (%): C 50.01 H 6.14 N 10.91

[α] D: + 2.53 ° (c = 1.02, H2O).

Example 19

2,2-Dimethyl-hexahydro-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine  hydrochloride

Starting from 1.30 g of 2-amino-2-methyl-1-propanol instead of D-alaninol and 2-aminoethanol instead of 3-amino-1-propanol and otherwise repeating the procedure of example 10, process 2, 0.30 g of the desired compound (white crystals) are obtained.

m.p. 279-282 ° C (decomp.).

Elementary Analysis (of C 17 H 23 N 3 O 2 S \ HCl \ H 2 O)

calculated (%): C 52.63 H 6.76 N 10.83 found (%): C 52.22 H 6.83 N 10.63

Example twenty

2,7-Dimethyl-hexahydro-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine  hydrochloride

Starting from 1.0 g of 3-amino-butan-1-ol instead of D-alaninol and 1-amino-2-propanol instead of 3-amino-1-propanol and otherwise repeating the procedure of example 10, process 2, 0.60 g of the desired compound (white crystals) are obtained.

m.p. 256-260 ° C (decomp.).

Elementary Analysis (of C 17 H 23 N 3 O 2 S \ HCl \ 1 / 2H 2 O)

calculated (%): C 53.89 H 6.65 N 11.09 found (%): C 54.19 H 6.57 N 11.14

Example twenty-one

(R) - (+) - hexahydro-5-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl-1H-1,4-diazepine hydrochloride

Starting from 0.83 g of 2-aminoethanol instead of D-alaninol Y 3- (R) -aminobutan-1-ol (synthesized according to J. Org. Chem. 42, 1650, 1977) instead of the 3-amino-1-propanol and otherwise repeating the procedure described in example 10, process 2, 0.41 g of the desired compound are obtained (crystals white).

m.p. 284-288 ° C.

Elementary Analysis (of C 16 H 21 N 3 O 2 S \ HCl \ cdot1 / 2H 2 O)

calculated (%): C 52.67 H 6.35 N 11.52 found (%): C 52.36 H 6.10 N 11.37

[α] D: + 3.61 ° (c = 1.05, H2O).

Example 22

(S) - (-) - hexahydro-5-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl-1H-1,4-diazepine hydrochloride

Starting from 0.50 g of 2-aminoethanol instead of D-alaninol Y 3- (S) -aminobutan-1-ol (synthesized according to J. Org. Chem. 42, 1650, 1977) instead of the 3-amino-1-propanol and otherwise repeating the procedure described in example 10, process 2, 0.27 g of the desired compound are obtained (crystals white).

m.p. 283-284 ° C.

Elementary Analysis (of C 16 H 21 N 3 O 2 S \ HCl \ H 2 O)

calculated (%): C 51.40 H 6.47 N 11.23 found (%): C 51.28 H 6.16 N 11.11

[α] D: -4.00 ° (c = 1.10, H2O).

Formulation example one

Composition (by ml) compound of example 6 3 mg sodium chloride 9 mg water for injection \ underline {cant. suf.} 1 ml

Manufacturing standard

The compound of example 6 and chloride are dissolved sodium in water for injection, the solution is filtered through a membrane filter (0.22 µm), the filtrate is packaged in ampoules and sterilized to obtain an aqueous injection.

Formulation example two

Composition (by vial) compound of example 9 3 mg little hand fifty mg

Manufacturing standard

The compound of example 9 and handyman dissolve in water for injection, the solution is filtered aseptically to through a membrane filter (0.22 µm), the liquid is packaged filtered in vials and lyophilized as usual to obtain a extemporaneous reconstitution injection.

Formulation example 3

Composition (180 mg per Tablet) compound of example 10 10 mg lactose 100 mg cornstarch 55 mg replacement hydroxypropylcellulose low 9 mg polyvinyl alcohol (hydrolyzed partial) 5 mg magnesium stearate one mg

Manufacturing standard

The previous components are mixed, except the polyvinyl alcohol and magnesium stearate, evenly and it granulate the wet mixture by an aqueous alcohol solution polyvinyl (binder), to obtain granules intended for compression. Stearate is added to the previous granules magnesium, they are mixed and, using a compression machine of tablets, the composition is molded to obtain oral tablets of 180 mg weight

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Formulation example 4

Composition (of 220 mg per capsule) compound of example 21 10 mg lactose 187 mg microcrystalline cellulose twenty mg magnesium stearate 3 mg \ overline {220 \ mg}

Manufacturing standard

The previous components are mixed and, using a capsule packaging machine, 220 mg of the mixture in each hard capsule, obtaining hard capsules.

Formulation example 5

Composition (for each g of granules) compound of example 9 10 mg lactose 880 mg lactose 70 mg hydroxypropyl cellulose 40 mg \ overline {1,000 \ mg

Manufacturing standard

The previous components are mixed, except the hydroxypropylcellulose, evenly, the mixture is kneaded using an aqueous solution of hydroxypropyl cellulose as binder and the dough is granulated with a granulating machine.

Test example one

Effect on the contraction of the rat aorta, induced by calcium ionophore

Rats are sacrificed (SD, males, age: 10 to 14 weeks) by exanguination with ether anesthesia and the aorta is isolated thoracic (approx. 3 cm). Once the fat and tissue are removed conjunctive cut the isolated aorta into slices 3 mm wide. The luminal wall of the aortic ring-shaped preparation is Rub to remove endothelial cells. The preparation in an isometric voltage transducer of a device Magnus that contains an organ bath medium and is loaded with a static tension of 1 g. The Magnus bath is maintained at 37 ° C subaireated with a mixture of gases (95% O2 and 5% CO2) and, after replacing the bathroom with a recent one at intervals of 20 minutes, the aortic preparation is balanced for 1 hour. I know add to this preparation calcium ionophore A23187 up to a final concentration of 1 µM and, once the response is confirmed constant contractile aortic preparation, the test compound cumulatively. The response of contraction-relaxation over time and it determines the 50% inhibitory concentration [IC50 (µM)] of the compound tested against vascular contraction induced by The A23187. As a result, the IC 50 values of the compounds of examples 4 and 9 are 1.1 and 0.74, respectively. For another side, the IC50 value of the positive control with fasudil hydrochloride is 5.1. The composition of the organ bath used in This test is 115.9 mM NaCl (same for others); KCl 5.9; CaCl2 2.5; MgCl2 1.2; NaH 2 PO 4 1.2; NaHCO 3 25.0; glucose 11.5. These components dissolve in water distilled and deionized. The pH of the saturated organ bath with said gas mixture is 7.4.

The compound of the invention relieves the response contractile blood vessels to calcium ionoforo and its effect is much greater than that of fasudil hydrochloride.

Test example two

Effect of increased blood flow in the cerebral artery rat mean

Rats are used (SD, males, age: 11-12 weeks) with urethane anesthesia, the head of each animal and an incision is made in the skin of the left buccal region. Once the buccinator muscle is removed, it exposes the zygomatic bone. In the cranial bone, immediately a hole is made above the middle cerebral artery (ACM) 5mm diameter drilling with an electric dental drill, which allows direct access to the ACM. The probe is placed (diameter: 1.0 mm) of a Doppler laser blood flow meter in the vicinity ACM immediate to track the flow change blood in the ACM. The compound to be tested is dissolved and diluted in saline solution and administered at a rate of 3 mg / kg by cannula from the femoral vein. The dose volume is adjusted to 0.1 ml / 100 mg and the total amount is administered in 30 seconds. The effect of each test compound is expressed as an increase percentage of blood flow from the baseline of the pre-administration and the duration of the action is expressed as a period of time until returning to baseline. As a result, the compound of the invention is equivalent to fasudyl hydrochloride in the percentage increase in blood flow, but is much higher than Fasudil hydrochloride in terms of duration of effect. For the Therefore, while the duration of the effect of fasudil hydrochloride is 2.3 minutes, that of the compound of example 9 and example 10 was 31.2 minutes and 36.0 minutes, respectively.

The compound of the invention has the effect of increase blood flow of the middle cerebral artery in the rat and the duration of this effect is much longer than the of fasudil hydrochloride.

Test example 3

Relief effect of cerebral vasospasm in the rat model of subarachnoid hemorrhage

If they fix rats (SD, males, age: 11-12 weeks) in prone position and undergo pentobarbital anesthesia, an incision is made in the center of the dorsocervical region. 0.20 ml are then extracted of cerebrospinal fluid from the cranial cavity through vertebral cervical paracentesis and 0.30 ml of other arterial blood rat is infused into the magna cistern (bulbocerebelosa). Later tilt your head down at an angle of 20 degrees for 20 minutes to let the blood distribute evenly from the basilar artery to the strings of Willis (of the breast lower sagittal). The next day the animal is fixed in position supine with urethane anesthesia, an incision is made in the cervical region for tracheal cannulation. Once exposed the occipital bone, an incision is made in the dura mater, the arachnoid and pia mater to expose the basilar artery. It covers the incision with liquid paraffin, the basilar artery is recorded by microscopic magnification on a video recorder and it determine the diameter of the basilar artery by analyzing the image. The test compound is administered in a dose of 3 mg / kg. from the left femoral vein for 1 minute. The effect of each compound is expressed in percentage increase in diameter over time of maximum relaxation and is compared to the baseline prior to administration. As a result, the compound of example 1 and the example 6 cause increases of 21.4% and 15.1%, respectively, in the diameter of the basilar artery, while the fasudil hydrochloride causes only an increase of 7.5%.

Test example 4

Relief effect of cerebral vasospasm in the canine model of subarachnoid hemorrhage

According to the method of Varsos et al. [J. Neurosurgery 58 , 11-17, 1983] the models of two canine hemorrhages are developed by two injections of autologous blood into the magna cistern. On the first day of the trial, a control angiogram of the basilar artery is recorded prior to medication, applying pentobarbital anesthesia. Then 4 ml of the cerebrospinal fluid from the magna cistern is extracted and the same volume of autologous blood is injected at a rate of 2 ml / min. After this blood injection, the head is tilted down at an angle of 30 degrees for 30 minutes to allow the blood to be distributed evenly across the Willis ropes. On the third day of the test, 4 ml of autologous blood are injected back into the magna cistern. On the seventh day, a cerebral angiogram with pentobarbital anesthesia is recorded to verify the induction of delayed cerebral vasospasm and drug evaluation is performed. The test compound, 3 mg / kg, is administered in the left femoral vein for 1 minute. Angiography is performed immediately after drug administration and after 10, 20, 30 and 60 minutes after the start of administration. The effect of each test compound is expressed as a percentage increase in the maximum section of the basilar artery compared to the baseline prior to administration. As a result, the percentage increases achieved with the compounds of example 6, example 9 and example 10 are 27.9%, 37.1% and 34.1%, respectively. On the other hand, the percentage increase with the positive control of fasudil hydrochloride is 9.1%. Therefore, if compared with fasudyl hydrochloride, the compound of the invention has a very potent reversal effect of vasospasm and allows recovering the diameter (caliber) of the basilar artery primarily to the baseline prior to treatment in the canine model of subarachnoid hemorrhage.

Test example 5

Prophylactic effect on cerebral vasospasm in rats

Rats are fixed (SD, males, age: 11-13 weeks) in prone position with anesthesia of pentobarbital and an incision is made in the center of the region dorsocervical Once 0.2 ml of cerebrospinal fluid from the cranial cavity through vertebral cervical paracentesis, it inject 0.30 ml artificial cerebrospinal fluid or blood Rat arterial in the cistern magna for 1 minute. Later tilt your head down at a 20 degree angle for 10 minutes to allow basilar arterial blood to be distributed evenly on the strings of Willis. The incision is treated with terramycin and is sutured and administered 10 mg intramuscularly of vicilina. After 24 hours the rat is anesthetized with urethane (1,1 g / kg, via i.p.) and is fixed supine. The tissue is fixed cerebral by retrograde perfusion with PBS / formalin from the descending aorta and is colored by infusion of 0.8 ml of Monastral Blue from the descending aorta. Once the brain, the basilar artery region is photographed and Determine the diameter of the basilar artery. The drug dissolves in saline solution and administered for 1 minute to the vein right femoral 20 minutes after blood injection.

As a result, the group treated with 3 mg / kg per via i. v. of the compound of example 10 shows no signs of vasospasm in the basilar artery, which otherwise is induced to 24 hours after the infusion of blood. With the positive control of fasudil hydrochloride, vasospasm of the artery is not observed basilar at 24 hours after blood injection in the treated group with 10 mg / kg i.v.

Test example 6

Effect of cerebral infarction in the rat model of occlusion transient middle cerebral artery

Male rats are anesthetized with halothane (breed Slc: SD, age: 7 weeks), an incision is made in the artery common carotid and a polyamide (nylon) thread is inserted from the incision, advancing through the internal carotid artery, to the origin of the middle cerebral artery. After this flow stop blood in the middle cerebral artery, anesthesia is terminated and 2 hours later the polyamide thread is removed for reperfusion. 6 hours after reperfusion, the brain is removed and stained with triphenyltetrazolium chloride (TTC) to identify the region infarcted The volume of the infarction in the cerebral cortex is determined and in the striatum. The drug is administered via intravenously for 1 minute in a total of 3 times, that is, 30 minutes before occlusion of the middle cerebral artery, immediately after occlusion and an hour later. I know administer saline as a control. The results are expressed in the form of mean ± standard error and the difference is analyzed significant by the Dunnett method. As a result, the compound of example 10, administered three times in a dose of 0.1 or 0.3 mg / kg each time and the compound of example 9, administered three times in a dose of 0.1 mg / kg, they display a significant protection against heart attack both in cortex cerebral as in the striatum. On the other hand, the fasudil hydrochloride administered three times in a dose of 5 mg / kg presents a significant anti-infarction effect only on the body fluted.

Test example 7

Effect on cerebral infarction in the rat model of occlusion of the middle cerebral artery by induced thrombosis photochemically (PIT)

Male rats are anesthetized (Slc race: SD, age: 7 weeks) by inhalation of a gas mixture (oxide nitrous / oxygen = 70/30) containing 1-2% of halothane and with an electric dental drill a hole is made 5 mm in diameter in the cranial bone, immediately above of the middle cerebral artery (ACM), in order to allow access Direct visual to the ACM. Rose is administered intravenously Bengal (RB), 20 mg / kg. After 5 minutes, using a manipulated three-dimensional, a light guide is placed next to the ACM (diameter 3.0 mm) as a light source to generate thrombosis in order to irradiate the artery with green light for 10 minutes. Past 24 hours the animals are beheaded and their brains are removed. I know prepare coronal sections at 2 mm intervals and stain with TTC and the volume of the infarction is determined in the entire brain. The drug is administered intravenously for 1 minute a total of 3 times, that is, immediately after finished irradiation with green light and 1 and 2 hours later. I know administer saline in the same way as a control. They express themselves the results in the form of mean ± standard error and are analyzed significant differences using the Dunnett method. How result, the compound of example 10 has an effect significant anti-infarction at a dose of 0.3 or 3 mg / kg x 3. By on the other hand, fasudil hydrochloride has an anti-infarct effect significant at a dose of 10 mg / kg x 3.

Test example 8

Acute toxicity

5-week-old male ddY mice are used age (5 per group), the drug to be tested is administered for 60 seconds from the caudal vein and the mortality of the animals for a later period of 24 hours. The drug of test is used dissolved and diluted in saline or in dimethyl sulfoxide (DMSO). As drugs to be tested, the compounds of example 1, example 6, example 7 and example 8 and fasudil hydrochloride. as a result, none of the compounds tested or fasudyl hydrochloride cause death in a dose of 40 mg / kg.

Industrial applicability

Therefore, if compared to the control or reference of fasudil hydrochloride, the compound of the invention displays a reversal activity of cerebral vasospasm enough at a much lower dose. In addition, the duration of the effect of the compound of the invention is also considerably more long The findings suggest the usefulness of the compound of the invention in the prevention and treatment of disorders cerebrovascular, especially brain tissue disorders due to cerebral vasospasm after cerebral hemorrhage. On the other hand, the compound of the invention has an effect cerebral vasodilator and a protective effect against death Ischemic neuronal, so it is useful for the management of sequelae of cerebral hemorrhage, cerebral infarction, attack Transient cerebral ischemic and cranial trauma.

Claims (9)

1. A compound of the following general formula [I] or a pharmaceutically acceptable salt thereof or a solvate of same 14 wherein in which R 1 means methyl or fluorine; R2 means hydrogen, hydroxy or halogen; R 3 means hydrogen, C 1 -C 6 alkyl or amidino; the atom or carbon atoms of the ring hexahydro-1H-1,4-diazepinyl they can be substituted by alkyl C_ {1} -C_ {6}. 2. The compound according to claim 1, in the that R2 is hydrogen. 3. The compound according to claim 1, in the that R3 is hydrogen. 4. A compound chosen from hexahydro-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine dihydrochloride, (S) - (+) - hexahydro-2-methyl-1 - [( 4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine hydrochloride, hexahydro-7-methyl-1 - [(4-
methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine dihydrochloride, hexahydro-5-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfo-
nil] -1H-1,4-diazepine dihydrochloride, hexahydro-2-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine hydrochloride, (R) - (-) - hexahydro-2-methyl-1 - [(4-methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine hydrochloride and (R) - (+) - hexahydro-5-methyl-1 - [(4- methyl-5-isoquinolinyl) sulfonyl] -1H-1,4-diazepine hydrochloride. 5. A pharmaceutical composition that, like active substance, contains a compound, a pharmaceutically salt acceptable or a solvate, claimed in claim 1. 6. A prophylactic or therapeutic drug for cerebrovascular disorders that, as active ingredient, contain the compound, pharmaceutically acceptable salt or solvate claimed in claim 1. 7. An inhibitor of cerebral vasospasms that, As active ingredient, it contains a compound, a salt pharmaceutically acceptable or a solvate, claimed in the claim 1. 8. A protector against neuronal death ischemic which, as active ingredient, contains a compound, a salt pharmaceutically acceptable or a solvate, claimed in the claim 1. 9. A prophylactic or therapeutic drug for transient cerebral ischemic attack that, as active ingredient, contains a compound, a pharmaceutically acceptable salt or a solvate, claimed in claim 1.